CRCNS: Investigating Brain Dynamics through the Lens of Statistical Mechanics

突触功能障碍被认为是阿尔茨海默氏症最早的大脑变化之一 疾病（AD），导致神经元回路中的过度兴奋。然而，网络变化与年龄有关 和性别倾向于与疾病神经病理学重叠，增加了分离的难度 与男性和女性正常衰老轨迹相关的疾病特异性改变。的确， AD对妇女的影响尤为严重，她们占所有被诊断患有AD的人的三分之二。 痴呆 利用静息状态fMRI连接体和弥散MRI衍生的结构连接体，我们将使用 新的杂交静息态结构连接体（rs-SC）研究兴奋-抑制平衡。最近， 使用一组认知正常的APOE-ε4携带者和年龄/性别匹配的非携带者， 表现出性别-年龄-表型的相互作用，随着年龄的增长，兴奋性明显增强 只在女性身上观察到，而在男性身上则没有。此外，女性携带者的过度兴奋开始表现为 年龄50岁的前扣带回，海马旁回和颞叶区域， 兴奋过度与空间学习过程中神经元资源的补偿性募集有关 记忆任务 在这个建议中，我们将描述1）兴奋-抑制平衡的性别特异性规范轨迹 使用人类连接组计划（HCP）数据，和2）改变兴奋-抑制平衡， 使用阿尔茨海默病神经成像倡议（ADNI）数据的异常衰老，以及3）进一步 在AD的纵向小鼠模型中测试和验证我们的过度兴奋框架。 相关性（参见说明）： 在这个建议中，我们将开发新的计算工具来表征超兴奋模式， 老化和阿尔茨海默氏病，并验证我们对人类数据的过度兴奋框架（ADNI和 HCP）以及AD的纵向小鼠模型。这将大大提高我们对AD的认识 并可能加速发现更强大的AD非侵入性成像生物标志物。

Synaptic dysfunction has been hypothesized to be one of the earliest brain changes in Alzheimer’s disease (AD), leading to hyper-excitation in neuronal circuits. However, network changes related to age and sex tend to overlap with disease neuropathology, increasing the difficulty of separating disease-specific alterations from those related to normal aging trajectories in males and females. Indeed, AD disproportionately affects women, who comprise two thirds of all persons diagnosed with AD dementia. Leveraging resting state fMRI connectome and diffusion MRI-derived structural connectome, we will use a novel hybrid resting-state structural connectome (rs-SC) to study excitation-inhibition balance. Recently, using a group of cognitively normal APOE-ε4 carriers and age/gender matched non-carriers we demonstrated a sex-by-age-by-phenotype interaction, with significant hyperexcitation with increasing age only observable in women, but not in men. Further, hyperexcitation in female carriers began to exhibit at age 50 in the anterior cingulate, parahippocampal gyrus and temporal lobe regions, and the degree of hyperexcitation is linked to compensatory recruitment of neuronal resources during a spatial learning memory task. In this proposal, we will characterize 1) sex-specific normative trajectories of excitation-inhibition balance using the Human Connectome Project (HCP) data, and 2) altered excitation-inhibition balance in abnormal aging using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, as well as 3) further test and validate our hyperexcitation framework in longitudinal mouse models of AD. RELEVANCE (See instructions): In this proposal, we will develop novel computational tools to characterize hyper-excitation patterns in aging and Alzheimer's Disease and validate our hyperexcitation framework on human data (ADNI and HCP) as well as longitudinal mouse models of AD. This will significantly improve our understanding of AD and potentially accelerate the discovery of more robust non-invasive imaging biomarkers of AD.